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Influence of baseline neurologic severity on disease progression and the associated disease-modifying effects of tafamidis in patients with transthyretin amyloid polyneuropathy.

ABSTRACT: BACKGROUND:Emerging evidence suggests that several factors can impact disease progression in transthyretin amyloid polyneuropathy (ATTR-PN). The present analysis used longitudinal data from Val30Met patients participating in the tafamidis (selective TTR stabilizer) clinical development program to evaluate the impact of baseline neurologic severity on disease progression in ATTR-PN. METHODS:A linear mixed-effects model for repeated measures (MMRM) was constructed using tafamidis and placebo data from the intent-to-treat Val30Met population of the original registration study as well as tafamidis data from the two consecutive open-label extension studies. The second extension study is ongoing, but a prospectively-planned interim analysis involving a cleaned and locked database was conducted (cut-off: December 31, 2014). Val30Met patients are presented by treatment groups as those who received tafamidis during the registration and open-label studies (T-T group), or who received placebo during the registration study and were switched to tafamidis in the open-label studies (P-T group). Neurologic functioning was assessed at baseline and subsequent visits using the Neuropathy Impairment Score-Lower Limbs (NIS-LL). The analysis focused on the disease trajectory over the first 18 months of treatment. RESULTS:The T-T (n?=?64) and P-T (n?=?61) cohorts were predominantly Caucasian and presented with early-stage neurologic disease (mean [standard deviation] baseline NIS-LL values were 8.4 [11.4] and 11.4 [13.5], respectively). The MMRM analysis demonstrated that baseline severity is an independent significant predictor of disease progression in addition to the treatment effect: patients with a lower baseline NIS-LL showed less progression than those with a higher baseline NIS-LL (p?

SUBMITTER: Amass L

PROVIDER: S-EPMC6296038 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Influence of baseline neurologic severity on disease progression and the associated disease-modifying effects of tafamidis in patients with transthyretin amyloid polyneuropathy.

Amass Leslie L Li Huihua H Gundapaneni Balarama K BK Schwartz Jeffrey H JH Keohane Denis J DJ

Orphanet journal of rare diseases 20181217 1

<h4>Background</h4>Emerging evidence suggests that several factors can impact disease progression in transthyretin amyloid polyneuropathy (ATTR-PN). The present analysis used longitudinal data from Val30Met patients participating in the tafamidis (selective TTR stabilizer) clinical development program to evaluate the impact of baseline neurologic severity on disease progression in ATTR-PN.<h4>Methods</h4>A linear mixed-effects model for repeated measures (MMRM) was constructed using tafamidis an ...[more]

PMID: 30558645

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Project description:To evaluate the efficacy and safety of 18 months of tafamidis treatment in patients with early-stage V30M transthyretin familial amyloid polyneuropathy (TTR-FAP).In this randomized, double-blind trial, patients received tafamidis 20 mg QD or placebo. Coprimary endpoints were the Neuropathy Impairment Score-Lower Limbs (NIS-LL) responder analysis (<2-point worsening) and treatment-group difference in the mean change from baseline in Norfolk Quality of Life-Diabetic Neuropathy total score (TQOL) in the intent-to-treat (ITT) population (n = 125). These endpoints were also evaluated in the efficacy-evaluable (EE; n = 87) population. Secondary endpoints, including changes in neurologic function, nutritional status, and TTR stabilization, were analyzed in the ITT population.There was a higher-than-anticipated liver transplantation dropout rate. No differences were observed between the tafamidis and placebo groups for the coprimary endpoints, NIS-LL responder analysis (45.3% vs 29.5% responders; p = 0.068) and change in TQOL (2.0 vs 7.2; p = 0.116) in the ITT population. In the EE population, significantly more tafamidis patients than placebo patients were NIS-LL responders (60.0% vs 38.1%; p = 0.041), and tafamidis patients had better-preserved TQOL (0.1 vs 8.9; p = 0.045). Significant differences in most secondary endpoints favored tafamidis. TTR was stabilized in 98% of tafamidis and 0% of placebo patients (p < 0.0001). Adverse events were similar between groups.Although the coprimary endpoints were not met in the ITT population, tafamidis was associated with no trend toward more NIS-LL responders and a significant reduction in worsening of most neurologic variables, supporting the hypothesis that preventing TTR dissociation can delay peripheral neurologic impairment.This study provides Class II evidence that 20 mg tafamidis QD was associated with no difference in clinical progression in patients with TTR-FAP, as measured by the NIS-LL and the Norfolk QOL-DN score. Secondary outcomes demonstrated a significant delay in peripheral neurologic impairment with tafamidis, which was well tolerated over 18 months.

Project description:BackgroundIn patients with transthyretin amyloid cardiomyopathy, tafamidis reduces all-cause mortality and cardiovascular hospitalizations and slows decline in quality of life compared with placebo. In May 2019, tafamidis received expedited approval from the US Food and Drug Administration as a breakthrough drug for a rare disease. However, at $225 000 per year, it is the most expensive cardiovascular drug ever launched in the United States, and its long-term cost-effectiveness and budget impact are uncertain. We therefore aimed to estimate the cost-effectiveness of tafamidis and its potential effect on US health care spending.MethodsWe developed a Markov model of patients with wild-type or variant transthyretin amyloid cardiomyopathy and heart failure (mean age, 74.5 years) using inputs from the ATTR-ACT trial (Transthyretin Amyloidosis Cardiomyopathy Clinical Trial), published literature, US Food and Drug Administration review documents, healthcare claims, and national survey data. We compared no disease-specific treatment ("usual care") with tafamidis therapy. The model reproduced 30-month survival, quality of life, and cardiovascular hospitalization rates observed in ATTR-ACT; future projections used a parametric survival model in the control arm, with constant hazards reduction in the tafamidis arm. We discounted future costs and quality-adjusted life-years by 3% annually and examined key parameter uncertainty using deterministic and probabilistic sensitivity analyses. The main outcomes were lifetime incremental cost-effectiveness ratio and annual budget impact, assessed from the US healthcare sector perspective. This study was independent of the ATTR-ACT trial sponsor.ResultsCompared with usual care, tafamidis was projected to add 1.29 (95% uncertainty interval, 0.47-1.75) quality-adjusted life-years at an incremental cost of $1 135 000 (872 000-1 377 000), resulting in an incremental cost-effectiveness ratio of $880 000 (697 000-1 564 000) per quality-adjusted life-year gained. Assuming a threshold of $100 000 per quality-adjusted life-year gained and current drug price, tafamidis was cost-effective in 0% of 10 000 probabilistic simulations. A 92.6% price reduction from $225 000 to $16 563 would be necessary to make tafamidis cost-effective at $100 000/quality-adjusted life-year. Results were sensitive to assumptions related to long-term effectiveness of tafamidis. Treating all eligible patients with transthyretin amyloid cardiomyopathy in the United States with tafamidis (n=120 000) was estimated to increase annual healthcare spending by $32.3 billion.ConclusionsTreatment with tafamidis is projected to produce substantial clinical benefit but would greatly exceed conventional cost-effectiveness thresholds at the current US list price. On the basis of recent US experience with high-cost cardiovascular medications, access to and uptake of this effective therapy may be limited unless there is a large reduction in drug costs.

Dataset Information

Influence of baseline neurologic severity on disease progression and the associated disease-modifying effects of tafamidis in patients with transthyretin amyloid polyneuropathy.

Publications

Influence of baseline neurologic severity on disease progression and the associated disease-modifying effects of tafamidis in patients with transthyretin amyloid polyneuropathy.

Similar Datasets

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